Early intervention needs to be a ‘team sport’ to curb checkpoint inhibitor-related irAEs
Early intervention is critical in managing patients with immune-related adverse events associated with cancer checkpoint inhibitor therapy, according to a presenter at the 2020 Interdisciplinary Autoimmune Summit.
“This is something that all of us will be drawn into in the near-term future,” Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology, and professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, said in his presentation. “It is not one disease, it is many diseases.”
Calabrese warned that all organ systems, ranging from the skin to the joints to the neurological and gastrointestinal systems, may be implicated. “Some resemble our autoimmune diseases, some do not, and some are entirely new,” he said.
But it is not just the broad nature of the complications that is of significant concern for Calabrese. “They are not rare,” he said.
He performed what he called “back-of-the-envelope calculations,” noting that there are 1.7 million cases of cancer each year in the U.S., according to the American Cancer Society. Somewhere between 40% and 45% of these cases are eligible for checkpoint inhibition using cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PDL-1) inhibition, which amounts to roughly 700,000 patients. If just 10% of those experience irAEs, the oncology, rheumatology, dermatology and gastrointestinal communities could be dealing with 70,000 patients.
In fact, Calabrese suggested that these are conservative estimates. “Grade 3 toxicities may be experienced by as many as 40% of patients receiving high-dose CTLA-4 inhibitors and 20% of those treated by PD-1 or PDL-1 inhibitors,” he said. “I don’t have to make the case that this is a disease for all of us.”
The skin is the most common organ affected by irAEs, according to Calabrese. “These events range from benign vitiligo to stage 4 diseases,” he said.
The gastrointestinal tract is also heavily affected, frequently in the form of colitis that resembles invasive bowel disease (IBD). “But GI colleagues tell us this is not IBD as we know it,” Calabrese said, noting different histology and endoscopic features. “The vast majority of these cases are mild, but when abdominal pain with blood or mucus in the stool is present, it can be a medical emergency.”
Of particular concern for Calabrese is the type of inflammatory arthritis associated with immune checkpoint inhibitors. “This can occur after discontinuation of checkpoint inhibitor therapy,” he said. “This is a chronic immune-mediated disease that can be severe and profound.”
In terms of potentially fatal toxicities, myocarditis is rare but accounts for a significant proportion of deaths in the irAE bucket. “Myocarditis is scary,” Calabrese said. In addition, a so-called “triple-M” series of events — myositis, myocarditis and myasthenia — has recently emerged. “We are learning about this.”
Pneumonitis and hepatitis are also sources of mortality, according to Calabrese. “These fatal toxicities are seen more fulminantly and rapidly in combination therapy and with CTLA-4,” he said. “We need to be aware of this as we craft our treatment plans moving ahead.”
As for questions that remain about the identification and management of irAEs, Calabrese stressed that non-oncologists who are familiar with managing immune-mediated conditions should see these patients “up front” in order to mitigate morbidity and mortality. “We now have treatment algorithms for every organ,” he said. “However, the algorithm to start with steroids and move to TNF inhibitors is out of date. We need to exploit this great armamentarium that we have.”
Identifying these patients early enough remains an obstacle, for one important reason. “Biomarkers to predict this are not in prime time yet,” Calabrese said.
It is for this reason that time is of the essence. “This is a team sport, and there needs to be a triage system,” he said. “We can’t afford to wait for weeks or months.”
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Calabrese LA. Checkpoint Inhibitor Therapy for Patients with Immune-Mediated Inflammatory Diseases. Presented at: Interdisciplinary Autoimmune Summit; July 10-12, 2020 (virtual meeting).